Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study

Hassan, Ahmed H.E.; Park, Kyung Tae; Kim, Hye Jin; Hj, Lee; Kwon, Yeong Ho; Hwang, Ji Young; Jang, Choon‐Gon; Chung, Jin-Gyun; Park, Ki Duk; Lee, Sang Joo; Oh, Seung Jun; Lee, Yong Sup

doi:10.1016/j.bioorg.2020.103834

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…A molecular docking study was performed using the crystal structure of TMPRSS2 deposited in Protein Data Bank (PDB: 7MEQ) employing standard computational protocols as described in Supplementary Materials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Methodsmentioning

confidence: 99%

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Hassan,

El-Sayed,

Yamamoto

et al. 2023

Viruses

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Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC50 value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.

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Section: Methodsmentioning

confidence: 99%

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Hassan,

El-Sayed,

Yamamoto

et al. 2023

Viruses

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“…Several CB 2 R ligands have been developed and evaluated (Ni et al, 2019b), including [ 11 C]NE40 (Vandeputte et al, 2012), [ 11 C]A-836339 (MDTC) (Pottier et al, 2017;Du et al, 2022), [ 18 F]MA3 (Attili et al, 2019), [ 18 F]FC0324 (Caillé et al, 2017), [ 18 F]JHU94620 (Moldovan et al, 2016), [ 18 F]LU13 (Gündel et al, 2022), [ 18 F]DM102 (Modemann et al, 2022), [ 18 F]CRA13 (Hassan et al, 2020), [ 11 C]RS-016 (Meletta et al, 2017), [ 11 C]RS-028 (Haider et al, 2018), [ 11 C]RSR-056 (Slavik et al, 2015), and [ 18 F]RoSMA-18-d6 (Haider et al, 2020). Thus far, only one in-human in vivo CB 2 R PET using [ 11 C]NE40 (Ahmad et al, 2016) in patients with AD and healthy controls has been reported, showing no group difference.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Kecheliev

Spinelli²,

Herde³

et al. 2022

Front. Aging Neurosci.

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Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aim to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAß mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for amyloid-ß deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB2R antibody was performed on brain slices from 17-month-old arcAß mice. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056, and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAß and non-transgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAß mice compared to NTL mice. CB2R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-ß deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAß mice. Ex vivo autoradiography showed that the specific binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAß and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAß and NTL mice at 6, 17, or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in a mouse model of AD-related cerebral amyloidosis, emphasizing CB2R as a suitable target for imaging neuroinflammation.

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“…CB 2 R has been shown to be increased and involved in Aβ pathology in 5×FAD [61,31] and J20 mouse models of AD amyloidosis [24] but reduced in the brains of 3×Tg mice (with both amyloid and tau pathology) and aging C57B6 mice [56]. Several CB 2 R ligands have been developed and evaluated [39], including [ 11 C]NE40 [54], [ 11 C]A-836339 (MDTC) [9,42], [ 18 F]MA3 [4], [ 18 F]FC0324 [6], [ 18 F]JHU94620 [35], [ 18 F]LU13 [14], [ 18 F]DM102 [34], [ 18 F]CRA13 [17], [ 11 C]RS-016 [32], [ 11 C]RS-028 [16], [ 11 C]RSR-056 [50] and [ 18 F]RoSMA-18-d6 [15]. Thus far, only one in-human in vivo CB 2 R PET using [ 11 C]NE40 [1] in patients with AD and healthy controls has been reported, showing no group difference.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of CB₂R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Kecheliev

Spinelli

Herde

et al. 2022

Preprint

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Neuroinflammation plays an important role in the pathophysiology of Alzheimer′s disease. The cannabinoid type 2 receptor (CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer′s disease. Here, we aimed to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAβ mouse model of Alzheimer′s disease amyloidosis. Immunohistochemical staining for Aβ deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB2R antibody was performed on brain slices from arcAβ mice 17 months of age. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056 and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAβ and nontransgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAβ mice compared to NTL mice. CB2R immunofluorescence was higher in the glial cells inside 6E10-positive amyloid-β deposits than peri-plaque with a low background. Ex vivo autoradiography showed that the binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAβ and NTL mice at 6, 17 and 24 months. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAβ and NTL mice at 6, 17 or 24 months. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in a model of AD-related cerebral amyloidosis/AD mouse model, emphasizing CB2R as a suitable target for imaging neuroinflammation.

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Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study

Cited by 7 publications

References 55 publications

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Evaluation of CB₂R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

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Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study

Cited by 7 publications

References 55 publications

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

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Evaluation of CB₂R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease